1 Stamcelleforskning- helbreder diabetes? Diabetes, beta cells and stem cell based therapy Ole D. Madsen Senior Principal Scientist Diabetes Biology Novo Nordisk A/S Honorary Professor in Diabetes Stem Cell Research University of Copenhagen
Agenda Diabetes and the Beta Cell. How to best preserve our beta cells? Role of Glp-1 and Insulin in beta cell homeostasis Cell based therapy Edmonton protocol Beta cells from stem cells
Diabetes - prevalence T1D: 5-10% of all cases T2D: 90-95% of all cases Diabetes currently affects 387 million people worldwide and this number is expected to rise to 592 million by 2035 1 death / 6 seconds (5.1 mill/yr) - ~2 newly diagnosed / 6 seconds (11 mill/yr) (latest edition of the IDF Diabetes Atlas)
Diabetes a worldwide challenge Need for improved treatment modalities We must change this grim forcast! 4 1 death every 7seconds 5 2 new patients every 7 seconds
Lifetime cost of diabetes We must focus on prevention Control and Monitoring (20-30%) Medicines Complications (70-80%) Improved glycemic control reduce the risk of developing complications Future goal: - normalization of blood sugar to eliminate the risk of developing complications American Diabetes Association: Economic costs of diabetes in the US in 2007. Diabetes Care (2008) 31(3):596-615.
Insufficient Mass of Functional -cells Cause Diabetes Diabetes; 2003 vol. 52 : 102-110? T2D (obese) Obesity normoglycemia? T1.5D (LADA) Normal / normoglycemia Edmonton protocol Islet transplantation + immunotherapy T1D (autoimmune) Madsen, APMIS 2005
Regulation of functional Beta cell mass - role of glucose (in mice) Neo-genesis Sensor of functional beta cell mass Function GSIS + incretin (Glp1) Cell death 15-04-27 Glucose Glucose Glucose is required for pancreatic endocrine cell formation (Scharfmann et al JBC 2007) Glucose Replication Glucose activates synthesis of proteins which suppress a constitutive apoptotic program in beta cells (Pipeleers JCI 1996) Slide No. 7 15-04-27 Glucose is the mitogenic hormone regulating homeostatic functional Beta Cell mass (Ferrer 2011) Madsen, APMIS 2005
Regulation of functional Beta cell mass - role of glucose (in mice) and insulin Neo-genesis Sensor of functional beta cell mass Function GSIS + incretin (Glp1) Cell death 15-04-27 Glucose Glucose Insulin receptors in -cells are critical for islet compensatory growth response to insulin resistance (Okada et al PNAS 2006) IR IRS2 Glucose Disruption of IRS-2 causes type 2 diabetes in mice (Withers et Nature 1998) + Insulin Replication Slide No. 8 15-04-27 Madsen, APMIS 2005
Regulation of functional Beta cell mass -role of Glp-1 Neo-genesis Sensor of functional beta cell mass Function GSIS + incretin (Glp1) 15-04-27 Cell death Slide no 9 JJ Holst Physiol Rev. 87(4):1409-39; 2007 Glp-1 Glp-1 Hui et al, Diabetes 50:785-796, 2001 Xu et al, Diabetes 48:2270-2276, 1999 Hui et al, Endocrinology 144:1444; 2003 Glp-1 Replication Farilla et al, Endocrinology 143:4397; 2002 Slide No. 9 15-04-27 Rewiew: Drucker D J Endocrinology 2003;144:5145-5148 Madsen, APMIS 2005
Presentation title Date 10 Insulin + Glp1? Neo-formation Sensor of functional beta cell mass GSIS + incretin (Glp1) Cell death MST1 deletion protects against diabetes Nature Medicine Volume: 20, Pages: 385 397 (2014) doi:10.1038/nm.3482 Glucose IR IRS2 Glucose MST1 Glucose + Insulin + Glp-1 Replication
HbA 1c over time DUAL trial Gough et al. Diabetologia 2013;56(Suppl. 1):S96(OR-219); Buse et al. Diabetes 2013;62(Suppl. 1):A16 8.5 8.0 Liraglutide (n=414) IDeg (n=413) IDegLira (n=833) HbA 1c (%) 7.5 7.0 HbA 1C EOT -1.28% 7.0% -1.44% 6.9% 6.5 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (weeks) Mean values (±SEM) based on FAS and LOCF-imputed data; EOT = end of trial; p-values are from an ANCOVA --- ADA/EASD HbA 1c target <7.0%; AACE HbA 1c target 6.5% -1.91%* 6.4% *p<0.0001 vs. IDeg and vs. Liraglutide
Insufficient Mass of Functional -cells Cause Diabetes window of prevention? Glp-1 + Insulin T2D (obese) Obesity normoglycemia T1.5D (LADA) Normal / normoglycemia Edmonton protocol T1D (autoimmune)
Insufficient Mass of Functional -cells Cause Diabetes window of prevention? Glp-1 + Insulin T2D (obese) Glp1 3mg Obesity normoglycemia T1.5D (LADA) Normal / normoglycemia Edmonton protocol T1D (autoimmune) April 22nd, 2015: Saxenda to be launched in USA for obesity treatment
14 Islet transplantation, a cure for diabetes? Naftanel MA, Harlan DM (2004) Pancreatic Islet Transplantation. PLoS Med 1(3): e58
Islet transplantation a real alternative Proof of principle: Cell therapy of T1D can restore euglycemia Before transplant. After transplant. Shapiro A.M.J et al.,n Engl J Med 2000;343:230-238. 7 Patients with severe type 1 diabetes. Inadequate glycemic control despite insulin therapy Recurrent hypoglycemic episodes No detectable C-peptide levels Multiple islet infusions Glucocorticoid-free immunosuppression
Edmonton protocol, 5-year follow-up Islet transplantation has greatly improved the life quality of 68% after 1 year patients with severe type I diabetes by relieving glucose 40% after 2 years instability and problems with hypoglycaemia 22% after 3 years ~7.5% after 5 years; >80% C-pep+ *) Ryan et al. Five-Year Follow-Up After Clinical Islet Transplantation. Diabetes, 2005. 54(7): p. 2060-2069 *)No recurrence of hypo s
1 7 A stem cell to beta cell project is based on cutting edge science but with significant challenges ahead Vision To find a cure for diabetes Aspiration Strategic plan and timeline To develop a product that maintains a normal blood glucose level without insulin treatment To pursue opportunity for β cell replacement therapy based on stem cell technology
Pluripotent stem cells, a potential source of beta cells for diabetes therapy Modified from Smith A. Annu. Rev. Cell Dev. Biol. 2001. 17:435 62 Modified from Jensen et al. J Cell Physiol. 2009 Jun;219(3):513-9
19 Project goal: To generate functional beta cells for replacement therapy as a treatment of diabetes Purification hescs Definitive Endoderm Pancreatic Endoderm Endocrine Progenitors Beta cell Source: Modified from Ole D Madsen & Palle Serup. Nature Biotechnology 24, 1481-1483 (2006)
Generation of definitive endoderm (DE), pancreatic endoderm (PE) and endocrine progenitors (EP) 20
Towards the generation of mature endocrine cells Slide no 21
Project goal: To generate functional beta cells for replacement therapy as a treatment of diabetes 22 Current focus Purification hescs Definitive Endoderm Pancreatic Endoderm Endocrine Progenitors Beta cell Source: Modified from Ole D Madsen & Palle Serup. Nature Biotechnology 24, 1481-1483 (2006)
Encapsulation and transplantation
Reconstitution of functional beta cell mass (and BMI in obesity) Insufficient Mass of Functional -cells Cause Diabetes may strongly reduce risk for developing diabetes complications window of prevention? Glp-1 + Insulin T2D (obese) Glp1 3mg Obesity normoglycemia T1.5D (LADA) Normal / normoglycemia Edmonton protocol T1D (autoimmune)
State of the art Stem cell derived beta cells for cell thearpy: Presentation title Date Pancreatic progenitors Viacyte is in Phase 1/2 clinical trial with VC01 (pancreatic progenitor cells that require up to 4 months of in vivo maturation before mature beta cells develop and become functional) Viacyte is a J&J controlled biotech Mature beta cells formed in vitro cure diabetes in T1D mice (requires an O 2 rich device before going into man) Kieffer-lab Vancouver: Nat Bio publication Oct 2014 Melton-lab Harvard: Cell publication Oct 2014 Kieffer-lab collaborate with Betalogics (a J&J controlled biotech) T2D (Diet induced diabetes/obesity) Kieffer-lab: Stem Cell Reports Apr 2015
Presentation title A cure for diabetes is within reach after scientists developed a treatment that eliminates the need for sufferers to inject insulin. The therapy involves a one-off transplant of laboratory-grown pancreatic cells, which scientists have finally succeeded in producing in large enough volumes to be able to treat patients. The cells worked normally for many months when implanted into mice, and the first human patients should undergo the treatment in the next few years Date 2 6 The advance is the culmination of 23 years of research by Doug Melton, pictured here with his wife Gail O'Keefe
State of the art 2 7
State of the art 2 8
Breakthroughs in the treatment of diabetes! 1920 J.L., Dec 15, 1922 Feb 15, 1923 Life saving treatment of patients with type 1 diabetes Unlimited supply Improved glucose control 2000 Improved -cell function The future: Regeneration of functional -cell mass Discovery of insulin Recombinant human insulin Insulin analogues GLP-1 Treatment Prevention Cure
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Presentation title Date 31 No dreamer is ever too small no dream is ever too big